Abstract
Microvascular endothelial cells (CMECs) oxidative damage resulting from hypoxia/reoxygenation (H/R) injury is responsible for microcirculation perfusion disturbances and the progression of cardiac dysfunction. However, few strategies are available to reverse such pathologies. Here, we studied the effects and mechanisms of liraglutide on CEMCs oxidative damage, focusing in particular on calcium overload-triggered free radical injury signals and the GLP-1R/PI3K/Akt/survivin survival pathways. The results indicate that H/R increased IP3R expression but reduced SERCA2a expression, which rapidly raised intracellular Ca2+ levels, subsequently leading to Ca2+-dependent xanthine oxidase (XO) activation, reactive oxygen species (ROS) production and the cellular apoptosis of CMECs. However, liraglutide pretreatment abrogated Ca2+-mediated oxidative apoptosis. Furthermore, liraglutide regulated the rate of IP3R/SERCA2a gene transcription and conserved SERCA2a-ATPase activity via the maintenance of ATP production under H/R, which drove excessive Ca2+ reflux to the sarcoplasmic reticulum (SR) and inhibited Ca2+ release from the SR, ultimately restoring Ca2+ homeostasis. Furthermore, the regulatory role of liraglutide on Ca2+ balance in conjunction with its up-regulation of superoxide dismutase, glutathione and glutathione peroxidase collectively scavenged the excess ROS under H/R. Moreover, we showed that liraglutide strengthened Akt phosphorylation and subsequently survivin expression. In addition, both the blockade of the GLP-1R/PI3K/Akt pathways and the siRNA-mediated knockdown of survivin abolished the protective effects of liraglutide on SR-Ca2+ function and CMECs oxidative apoptosis. In summary, this study confirmed that H/R induced CMECs oxidative damage through the SR-Ca2+–XO–ROS injury signals and that liraglutide pretreatment may suppress such CMECs damage through the PI3K/Akt/survivin pathways.
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